This project addresses the regulation of gonadotropin secretion by the hypothalamic neuropeptide, gonadotropin releasing hormone (GnRH), and the signaling systems that control the release of GnRH from hypothalamic neurons. The GnRH receptor cDNA was cloned from a pituitary gonadotroph cell line and found to encode a seven transmembrane protein that is unique among G protein-coupled receptors in lacking a C-terminal cytoplasmic domain. The receptor is expressed not only in the pituitary gland and gonads but also in the GnRH-producing neurons of the hypothalamus, in which GnRH agonists suppressed basal pulsatile secretion and induced infrequent but massive episodes of GnRH release. Thus, GnRH exerts autocrine actions on its own secretion and promotes the synchronized discharge of GnRH in a manner that reflects the genesis of the ovulatory GnRH surge in vivo. In pituitary gonadotrophs, GnRH receptors activate oscillatory Ca2+ signaling by promoting Ca2+ release from internal stores and influx through L-type calcium channels. The mechanism of agonist-induced calcium oscillations was shown to include an essential action of Ins(1,4,5)P3 on the initiation of the oscillatory response and on the control of its frequency. However, the maintenance of the oscillating Ca2+ signal does not require continued elevation of Ins(1,4,5)P3. We have proposed that the Ins(1,45)P3-sensitive channels in the endoplasmic reticulum are tonically inhibited by high intraluminal calcium levels, and that Ins(1,4,5)P3 surmounts such inhibition by promoting calcium discharge. At a critical level of calcium discharge, repetive calcium transients are generated by an autocatalytic mechanism that does not require a sustained increase in Ins(1,4,5)P3 production.